Neuropathic pain is a form of chronic pain resulting from injury or disease to the peripheral or central nervous system that often persists long after initial injury has resolved. Multiple mechanisms are believed to play a role in the maintenance of the persistent pain state and therefore effective treatment of neuropathic pain often utilizes drugs that alternatives to prototypical and currently used mu opioid analgesics.
While mu opioid analgesics are commonly used to treat certain types of pain, their use for the treatment of neuropathic pain is limited due to concerns of addiction and tolerance that may develop following the chronic use of high doses of those compounds. Such effects can be amplified when mu opioid analgesics are used in treating patients suffering from neuropathic pain because the doses used are often increased over those used to treat nociceptive pain. Rodriguez-Munoz (2012) Neuropsychophamacology 37:338-349. Further, the NMDA receptor is believed to negatively regulate the ability of mu opioid agonists to alleviate neuropathic pain. It has been postulated that bifunctional drugs, e.g., those acting as both mu opioid agonists and NMDA receptor agonists could provide a new avenue for treating neuropathic pain.
Levorphanol is a synthetic opioid that is approved for the treatment of pain that has demonstrated some promise in the treatment of neuropathic pain. At a molecular level, levorphanol binds to the mu opioid receptor and also shows activity at inhibiting the serotonin transporter (SERT), norepinephrine transporter (NERT), and as an antagonist of the NMDA receptor. The multimodal mechanism of action at alleviating pain suggests that levorphanol could be potentially useful in the treatment of neuropathic pain. In this regard, levorphanol was shown to be effective in reducing neuropathic pain in a Phase II clinical study although its use was associated with severe dose-limiting side effects. Rowbotham et al. (2003) N. Engl. J Med. 348:13.
Although not bound by theory, it is believed that compounds designed to act as both mu opioid agonists and NMDA antagonists are candidates for treating patients suffering from neuropathic pain. In addition, because the dose-limiting opioid side effects are mediated centrally, it is hypothesized that reducing the entry of a compound across the blood-brain barrier may achieve two benefits. First, reducing entry of a compound across the blood-brain barrier would likely reduce or eliminate one or more central side effects. Second, reducing entry of a compound across the blood-brain barrier by peripheral restriction would allow for significantly higher doses to be used as a result of reduced or eliminated central side effects.
The incorporation of a poly(ethylene glycol) moiety into a small molecule scaffold has been utilized to modify the rate of CNS entry of several classes of molecules. U.S. Patent Application Publication No. 2005/0136031 and U.S. Patent Application Publication No. 2010/0048602. The sites of incorporation and further modifications to the molecules, however, have differing effects on the overall activity and pharmacological properties of the resulting molecule.
As such, there remains a need for drugs for the treatment of patients suffering from neuropathic pain, including those that act as mu opioid agonists with fewer or lessened side effects associated with mu opioid agonist-based therapy. Further, those compounds that effectively act as mu opioid agonists while antagonizing the NMDA receptor are of particular interest. The present invention seeks to address these and other needs.